Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)

Chronic GVHD Clinical Trial

Official title:

A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN Protocol #0801)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01106833
• Other study ID #: BMTCTN0801
• Secondary ID: U01HL069294BMT C
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 2010
• Est. completion date: June 2018

Study information

• Verified date: November 2018
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed as a combined Phase II/III, randomized, open label, multicenter, prospective comparative study of sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients will be stratified by transplant center and will be randomized to an experimental arm of one of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.

Description:

Background: Chronic GVHD is a medical condition that can become very serious. Chronic GVHD is a common development after allogeneic transplant that occurs when the donor cells attack and damage tissues. The primary purpose of this study is to compare treatment regimens that contain sirolimus without a calcineurin inhibitor to a comparator regimen of sirolimus with a calcineurin inhibitor and evaluate how well chronic GVHD responds to treatment. The combinations of medications in this study are:

• Sirolimus + calcineurin inhibitor + prednisone

• Sirolimus + prednisone

The goal is to select a treatment regimen for further comparison in the Phase III trial.

Design Narrative: The intent is to enroll subjects at the start of initial therapy for chronic GVHD, or before their chronic GVHD is refractory to glucocorticoid therapy, or is chronically dependent upon glucocorticoid therapy and multiple secondary systemic immunosuppressive agents. Patients will be stratified by transplant center and will be randomized to one of two arms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 151
• Est. completion date: June 2018
• Est. primary completion date: February 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Suitable candidates are patients with classic chronic GVHD or overlap syndrome (classic chronic plus acute GVHD)that is: a)Previously untreated (newly diagnosed) as defined by having received < 14 days of prednisone (or equivalent) before enrollment/randomization to study therapy; b)Previously treated but inadequately responding after = 16 weeks of initial therapy with prednisone and/or calcineurin inhibitor (CNI) ± additional non-sirolimus agent (started at the time of chronic GVHD diagnosis).

• Patient or guardian willing and able to provide informed consent.

• Stated willingness to use contraception in women of childbearing potential.

• Stated willingness of patient to comply with study procedures and reporting requirements.

Exclusion Criteria:

• Patients with late persistent acute GVHD or recurrent acute GVHD only.

• Inability to begin prednisone therapy at a dose of greater than 0.5 mg/kg/day.

• Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or treatment of acute GVHD is acceptable).

• Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with prednisone at = 0.25 mg/kg/day (or equivalent) ± additional agents.

• Receiving therapy for chronic GVHD for more than 16 weeks.

• Invasive fungal or viral infection not responding to appropriate antifungal or antiviral therapies.

• Inadequate renal function defined as measured creatinine clearance less than 50 mL/min/1.73 m^2 based on the Cockcroft-Gault formula (adults) or Schwartz formula (age less than or equal to 12 years). Adults: estimated creatinine clearance rate (eCCr) (mL/min/) = (140 - age) x mass (kg) x (0.85 if female)/72 x serum creatinine (mg/dL; Creatinine clearance (mL/min/1.73m^2) = eCCr x 1.73/Body Surface Area (BSA) (m^2); Children: eCCr (mL/min/1.73 m^2) = k x height (cm) / serum creatinine (mg/dL) k = 0.33 (pre-term), 0.45 (full term to 1 year old), 0.55 (age 1-12 years).

• Inability to tolerate oral medications.

• Absolute neutrophil count less than 1500 per microliter.

• Requirement for platelet transfusions.

• Pregnancy (positive serum ß-HCG) or breastfeeding.

• Receiving any treatment for persistent, progressive or recurrent malignancy.

• Progressive or recurrent malignancy defined other than by quantitative molecular assays.

• Known hypersensitivity to sirolimus.

Related Conditions & MeSH terms

• Chronic GVHD
• Graft vs Host Disease

Intervention

Drug:
• Sirolimus + calcineurin inhibitor + prednisone
The target serum level for sirolimus is 3-12 ng/mL. The target serum level for tacrolimus is 5-10 ng/mL. The target serum level for cyclosporine is 120-200 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.
• Sirolimus + prednisone
The target serum level for sirolimus is 3-12 ng/mL. Prednisone is administered initially as a single early morning dose of 1 mg/kg/day (or equivalent). If prednisone at a dose of 1 mg/kg/day (or equivalent) is contraindicated, patients may begin prednisone between 0.5-1 mg/kg/day.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Blood & Marrow Transplant Program at Northside Hospital	Atlanta	Georgia
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina Hospital at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Chicago	Chicago	Illinois
United States	Jewish Hospital BMT Program	Cincinnati	Ohio
United States	University Hospitals of Cleveland/ Case Western	Cleveland	Ohio
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine (Shands)	Gainesville	Florida
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas/MD Anderson CRC	Houston	Texas
United States	University of Kansas Hospital	Kansas City	Kansas
United States	University of California San Diego Medical Center	La Jolla	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	University of Oklahoma Medical Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University (A) and (P)	Portland	Oregon
United States	Virginia Commonwealth University/MCV Hospitals	Richmond	Virginia
United States	Mayo Clinic	Rochester	New York
United States	Washington University, Barnes Jewish Hospital	Saint Louis	Missouri
United States	Texas Transplant Institute	San Antonio	Texas
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Stanford Hospital and Clinics	Stanford	California

Sponsors (5)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Blood and Marrow Transplant Clinical Trials Network, National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Marrow Donor Program

Country where clinical trial is conducted

United States, 

References & Publications (1)

Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Participants With Treatment Success	Treatment success was evaluated at 6 months in Phase II and is defined as a complete or partial response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death. In Phase III, treatment success was evaluated at 24 months and is defined as a complete response without secondary systemic immunosuppressive therapy and no recurrent malignancy or death.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Overall Survival	Overall survival is defined as survival of death from any cause.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Progression-free Survival	Progression-free Survival is defined as survival without malignancy relapse. Relapse and death are considered failures for this endpoint.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Failure-free Survival	Failure-free Survival is defined as survival without malignancy progression or initiation of secondary therapy for chronic GVHD. Progression, initiation of secondary therapy for chronic GVHD, and death are considered failures for this endpoint.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Relapse	Relapse is defined as recurrence of the primary malignancy. Death is considered a competing risk for this endpoint.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Secondary Immunosuppressive Therapy Initiated	The percentage of participants initiating secondary immunosuppressive therapy for chronic GVHD is described. Death is considered a competing risk for this endpoint.	6 months and 24 months post-randomization
Secondary	Percentage of Participants With Discontinuation of Systemic Immunosuppressive Therapy at Two Years	The percentage of participants discontinuing all systemic immunosuppressive therapy by two years post-randomization is described. Death is considered a competing risk for this endpoint.	2 years post-randomization
Secondary	Prednisone Dose	Daily dose of prednisone is described by treatment arm at baseline, 6 months, and 1 year post-randomization.	Baseline, 6 months, and 1 year post-randomization
Secondary	Change in Prednisone Dose From Baseline	Change in the daily dose of prednisone from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.	6 months and 1 year post-randomization
Secondary	Serum Creatinine Level	Creatinine level is described by treatment arm at baseline, 6 months, and 1 year post-randomization.	Baseline, 6 months, and 1 year post-randomization
Secondary	Change in Serum Creatinine Level From Baseline	Change in creatinine level from baseline, the time of randomization, is described by treatment arm at 6 months and 1 year post-randomization.	6 months and 1 year post-randomization
Secondary	Patient-reported Chronic GVHD Severity	Each patient's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
Secondary	Provider-reported Chronic GVHD Severity	Each patient's care provider's perception of the severity of the chronic GVHD was collected at baseline and at 6 months, 1 year, and 2 years post-randomization. Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
Secondary	NIH Consensus Criteria Chronic GVHD Severity	Chronic GVHD severity was determined at baseline and at 6 months, 1 year, and 2 years post-randomization per the 2005 NIH Consensus Criteria (Filipovich et al. 2005). Severity is categorized as none, mild, moderate, and severe.	Baseline, 6 months, 1 year, and 2 years post-randomization
Secondary	SF-36 Physical Component Summary	The Medical Outcome Study SF-36 Physical Component Summary (PCS) is a subscale of the SF-36 intended to measure physical well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
Secondary	SF-36 Mental Component Summary	The Medical Outcome Study SF-36 Mental Component Summary (MCS) is a subscale of the SF-36 intended to measure mental well-being. It is scored on a scale of 0-100, with higher scores indicating higher levels of well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization
Secondary	FACT-BMT Score	The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has 37 questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being.	Baseline, 2 months, 6 months, 1 year, and 2 years post-randomization

External Links

•   BMT CTN Website
•   National Marrow Donor Program